Aging in a Dish: iPSC-Derived and Directly Induced Neurons for Studying Brain Aging and Age-Related Neurodegenerative Diseases

Abstract

Age-associated neurological diseases represent a profound challenge in biomedical research as we are still struggling to understand the interface between the aging process and the manifestation of disease. Various pathologies in the elderly do not directly result from genetic mutations, toxins, or infectious agents but are primarily driven by the many manifestations of biological aging. Therefore, the generation of appropriate model systems to study human aging in the nervous system demands new concepts that lie beyond transgenic and drug-induced models. Although access to viable human brain specimens is limited and induced pluripotent stem cell models face limitations due to reprogramming-associated cellular rejuvenation, the direct conversion of somatic cells into induced neurons allows for the generation of human neurons that capture many aspects of aging. Here, we review advances in exploring age-associated neurodegenerative diseases using human cell reprogramming models, and we discuss general concepts, promises, and limitations of the field.

Next‐generation disease modeling with direct conversion: a new path to old neurons

“…We expect such criteria to become more and more popular, extending our knowledge of cell identity, and that they will eventually largely replace classical means of neuronal characterization. The rejuvenation effect of iPSC reprogramming is a major drawback when attempting to model late-onset diseases [17,157,158], and artificial induction of the factor age by overexpressing progerin [151], shortening of telomeres [159], or exposing cells to age-related stressors [12,160] is an upcoming and widely used strategy to elicit a relevant phenotype in iPSC models for neurodegenerative diseases [12,148,[161][162][163]. In vitro generation of patient-specific neurons from iPSCs for modeling diseases of the brain has evolved into an integral part of neuroscience [144][145][146], and employing human iPSC technology to investigate aspects of age-related neurodegenerative diseases in a patient-specific genetic context at a cellular level has yielded important human neuron-specific insights [147][148][149][150].…”

“…In vitro generation of patient-specific neurons from iPSCs for modeling diseases of the brain has evolved into an integral part of neuroscience [144][145][146], and employing human iPSC technology to investigate aspects of age-related neurodegenerative diseases in a patient-specific genetic context at a cellular level has yielded important human neuron-specific insights [147][148][149][150]. 2) [12,17,157]. 2) [10,[151][152][153][154][155][156].…”

“…This boom in applications can be mostly attributed to the explosion of new technologies tailored to iPSC-based systems, most of which are also suitable for directly converted cells. These technologies encompass tools and strategies to harness human donor/patient-specific cells for basic human biology research [9][10][11][12], disease modeling [13][14][15][16][17], drug development and safety [18][19][20][21], or cell replacement strategies [22]. Although on first sight iNs might appear as 'just another way' to generate neurons in the dish, there are important technical and conceptual differences between iPSC-derived neurons and iNs to be noted.…”

“…2) [10,[151][152][153][154][155][156]. The rejuvenation effect of iPSC reprogramming is a major drawback when attempting to model late-onset diseases [17,157,158], and artificial induction of the factor age by overexpressing progerin [151], shortening of telomeres [159], or exposing cells to age-related stressors [12,160] is an upcoming and widely used strategy to elicit a relevant phenotype in iPSC models for neurodegenerative diseases [12,148,[161][162][163]. Direct iN conversion of human fibroblasts from elderly human patients and healthy donors into iNs circumvents this issue and has attracted broad attention.…”

Mechanisms of cellular rejuvenation

“…Interestingly, although iPSC-based reprogramming followed by differentiation erases aging hallmarks, direct reprogramming into neurons does not [56]. Comparing neurons generated by transdifferentiation or classical reprogramming from fibroblasts from individuals ranging from 0 to 89 years demonstrated a clear difference: whereas, iN retained the age-dependent expression differences, they were erased in iPSCs and remained transcriptionally rejuvenated upon differentiation into neurons [57].…”